From chemistry-request@server.ccl.net Mon May 15 16:22:13 2000 Received: from mailhost.msi.com (fire.msi.com [146.202.0.242]) by server.ccl.net (8.8.7/8.8.7) with ESMTP id QAA16337 for ; Mon, 15 May 2000 16:22:13 -0400 Received: (from daemon@localhost) by mailhost.msi.com (980427.SGI.8.8.8/970903.SGI.AUTOCF) id NAA06257 for ; Mon, 15 May 2000 13:19:43 -0700 (PDT) Message-Id: <200005152019.NAA06257@mailhost.msi.com> Received: from osman-pc.msi.com(146.202.7.202) by mailhost via smap (V2.0) id xma006252; Mon, 15 May 00 13:19:19 -0700 X-Sender: osman@146.202.6.217 X-Mailer: QUALCOMM Windows Eudora Pro Version 4.0.1 Date: Mon, 15 May 2000 13:18:42 -0700 To: CHEMISTRY@ccl.net From: "Osman F. Guner" Subject: Examples for late drug candidate failures due to ADME Mime-Version: 1.0 Content-Type: text/plain; charset="iso-8859-1" Content-Transfer-Encoding: 8bit X-MIME-Autoconverted: from quoted-printable to 8bit by server.ccl.net id QAA16338 Are there any famed examples of late failures of drug candidates (or drugs)? Any additional information and/or references related to the cost associated with those failures will also be useful. This is for a preliminary research on a potential symposium. I will be happy to summarize the responses to the list. Thx...Osman --- Osman F. Güner, Ph.D. Director, Lead Identification & Optimization Molecular Simulations Inc. (858) 799-5341 osman@msi.com http://www.msi.com From chemistry-request@server.ccl.net Tue May 16 09:39:06 2000 Received: from cliff.niehs.nih.gov (root@cliff.niehs.nih.gov [157.98.8.7]) by server.ccl.net (8.8.7/8.8.7) with ESMTP id JAA20791 for ; Tue, 16 May 2000 09:39:05 -0400 Received: from trollope.niehs.nih.gov (trollope.niehs.nih.gov [157.98.13.26]) by cliff.niehs.nih.gov (8.9.1a/8.9.1/NIEHS-1.18) with ESMTP id JAA12400 for ; Tue, 16 May 2000 09:38:53 -0400 Received: by trollope.niehs.nih.gov with Internet Mail Service (5.5.2650.21) id ; Tue, 16 May 2000 09:38:56 -0400 Message-ID: <4D693F933DD8D311A18C00E018B0057652C778@trollope.niehs.nih.gov> From: "Bienstock.Rachelle" To: "'CHEMISTRY@ccl.net'" Subject: HEME parameters Date: Tue, 16 May 2000 09:38:49 -0400 MIME-Version: 1.0 X-Mailer: Internet Mail Service (5.5.2650.21) Content-Type: text/plain; charset="iso-8859-1" Hi, Does anyone know if there are readily available force field parameters for hemes? I searched the ccl archives and saw reference to AMBER parameters that were ftp-able from David Case at Scripps, however, when I went to the ftp site and looked in the pub directory, the AMBER heme parameters were no longer there. In the 970 MSI distribution, there is a cvff_heme.frc file in the irix6m3/bioxym_lib directory, however, I have been cautioned by Jodi Shaulsky, Senior Scientist Scientific Support MSI, not to use these parameters as they are not "validated" and there are missing "parameters". Any recommendations appreciated and will be summarized for the list. Thanks, Rachelle Dr. Rachelle J. Bienstock Molecular Modeling and Structural Biochemistry NIH NIEHS / ITSS P.O. Box 12233 MD F0-01 Research Triangle Park, NC 27709 Telephone: (919) 541-3397 E-mail: biensto1@niehs.nih.gov Office: Room F091 From chemistry-request@server.ccl.net Tue May 16 13:59:19 2000 Received: from postal.ucc.uno.edu (postal.ucc.uno.edu [137.30.1.80]) by server.ccl.net (8.8.7/8.8.7) with ESMTP id NAA00811 for ; Tue, 16 May 2000 13:59:18 -0400 Received: from CONVERSION-DAEMON by postal.ucc.uno.edu (PMDF V5.2-32 #39187) id <0FUN00J01Z3D60@postal.ucc.uno.edu> for chemistry@ccl.net; Tue, 16 May 2000 12:54:49 -0500 (CDT) Received: from uno.edu (cuzco.chem.uno.edu [137.30.57.85]) by postal.ucc.uno.edu (PMDF V5.2-32 #39187) with ESMTP id <0FUN00FLRZ3CMF@postal.ucc.uno.edu> for chemistry@ccl.net; Tue, 16 May 2000 12:54:49 -0500 (CDT) Date: Tue, 16 May 2000 12:51:13 -0500 From: Monica Concha Subject: Help To: "chemistry@ccl.net" Message-id: <39218A8C.13B1D20B@uno.edu> Organization: University of New Orleans Hi all, I have been trying to optimize the vanadium dimer with multiplicity of 3, using various dft methods. The problem is that depending on the initial bond length, the dimer optimizes to different bond lengths with different energies, and differ s**2 values. The bond lengths only differ by about 0.01 Angstroms but the energies differ by 35 kcal. The odd thing is that the lowest energy corresponds to an s**2 value of 2.55 rather than the expected value of 2.0. Any suggestions? -- Monica C. Concha Research Associate Dept. Of Chemistry University of New Orleans New Orleans LA 70148 E-mail mconcha@uno.edu From chemistry-request@server.ccl.net Tue May 16 19:10:55 2000 Received: from mta6.snfc21.pbi.net (mta6.snfc21.pbi.net [206.13.28.240]) by server.ccl.net (8.8.7/8.8.7) with ESMTP id TAA02232 for ; Tue, 16 May 2000 19:10:54 -0400 Received: from firstprinciples.com ([63.192.67.78]) by mta6.snfc21.pbi.net (Sun Internet Mail Server sims.3.5.2000.01.05.12.18.p9) with ESMTP id <0FUO001I5DODMV@mta6.snfc21.pbi.net> for chemistry@ccl.net; Tue, 16 May 2000 16:09:50 -0700 (PDT) Date: Tue, 16 May 2000 16:03:35 -0700 From: "Jason K. Perry" Subject: Re: CCL:Help To: Monica Concha Cc: "chemistry@ccl.net" Message-id: <3921D3C6.476FC98C@firstprinciples.com> Organization: First Principles Research, Inc. MIME-version: 1.0 X-Mailer: Mozilla 4.61 [en]C-PBI-NC404 (Win98; I) Content-type: text/plain; charset=us-ascii Content-transfer-encoding: 7bit X-Accept-Language: en References: <39218A8C.13B1D20B@uno.edu> Hi Monica, If you haven't done much work with metal clusters before, you're quickly going to find out they are much tougher than simple organics. The problem is there are lots of low-lying excited states arising from low overlap of the incomplete d shells. In the case of V2, you have two dominantly s1d4 atoms bonded to one another, with the other atomic states, d5 and s2d3, probably mixing in. This gives you a large number of possible spin and orbital combinations to work with. As for your DFT calculations, it's a given that you have to specify spin. But in these cases, you may also have to play with the orbital occupations in the initial guess. It's very easy for most codes to converge to excited states of these molecules. The only solid solution is to be very thorough. You've found two different triplet states already, but it might not be guaranteed that either is actually the lowest energy triplet (or the ground state for that matter!). Be aware of what states (d orbital occupations) are being converged. Try switching around the orbital occupations and converging some other states. Most codes offer some way of doing this either with the default initial guess or with a restart file. If you're worried about spin contamination, you might want to try a restricted open-shell approach. I'd suggest sticking with unrestricted, though. In this case, I'd probably turn off any symmetry restrictions to allow the spins to localize. I haven't reviewed the literature on V2, but I'd guess the ground state is singlet with one V alpha-spin s1d4 and the other beta-spin s1d4. The strong exchange interaction between the d orbitals should be enough to localize the spin. But low-lying spin states could extend up to nonet states. Good Luck, Jason Perry Monica Concha wrote: > I have been trying to optimize the vanadium dimer with multiplicity > of 3, using various dft methods. The problem is that depending on the > initial bond length, the dimer optimizes to different bond lengths with > different energies, and differ s**2 values. The bond lengths only > differ > by about 0.01 Angstroms but the energies differ by 35 kcal. The odd > thing is that the lowest energy corresponds to an s**2 value of 2.55 > rather than the expected value of 2.0. Any suggestions? -- .................................................................. Jason K. Perry, Ph.D. First Principles Research, Inc. 8391 Beverly Blvd., #171, Los Angeles, CA 90048 phone (323) 465-9572 FAX (323) 465-2805 http://www.firstprinciples.com .................................................................. From chemistry-request@server.ccl.net Tue May 16 23:29:45 2000 Received: from hotmail.com (oe30.law3.hotmail.com [209.185.240.23]) by server.ccl.net (8.8.7/8.8.7) with SMTP id XAA03330 for ; Tue, 16 May 2000 23:29:44 -0400 Received: (qmail 2057 invoked by uid 65534); 17 May 2000 03:27:39 -0000 Message-ID: <20000517032739.2056.qmail@hotmail.com> X-Originating-IP: [161.142.78.83] From: "Yeoh Hak Koon" To: "CCL" Subject: Summary of frontier orbital enquiry Date: Wed, 17 May 2000 11:21:22 +0800 Dear Colleagues, A summary for whoever interested : -------------------------------------------------------------------------= ------- My questions on Fukui's frontier orbital theory : (a) Is his theory still valid, i.e. not overtaken by another better theory? (b) What improvements had gone into the treatment of superdelocalizability? (c) Has this theory been successful in more complicated molecules like metal complex catalysts? -------------------------------------------------------------------------= ------- I got responses mainly on part (a), thanks to Peder Svensson, Eldbj=F8rg Sofie Heimstadas (& Alan Shusterman's forwarded email), Andreas Klamt and E. Lewars. Answers follow (edited and abridged) : 1.. Basic assumption for applicability : the transition state must be reactant-like. However, "one could of course draw conclusions from the FOs of the product if one knows that the TS is product-like". 2.. Superdelocalizability is available on MOPAC, and is used in QSAR, but interpretation (+/- signs) and superiority was not certain. 3.. Superdelocalizability must take into account the MO energies of the interacting orbitals in the nucleophile and the electrophile to be truthful to its original definition. 4.. An improved concept for local frontier orbital descriptors is in Chemosphere 1993, 26, 1273-1289 5.. However, the frontier orbital concept was criticised on not having a real theoretical basis. Criticisms by M J S Dewar are in "A Semiempirical Life", ACS, Washington DC, 1992, pp. 162-163; and THEOCHEM, 1989, 200, 301. -------------------------------------------------------------------------= ------- So, if you have more to add to parts (b) and (c), please! Best regards, H. K. Yeoh